title: Systemic administration of Abeta mAb reduces retinal deposition of Abeta and activated complement C3 in age-related macular degeneration mouse model.
abstract: Age-related macular degeneration (AMD) is a leading cause of legal blindness in the Western world. There are effective treatments for the vascular complications of neo-vascular AMD, but no effective therapies are available for the dry/atrophic form of the disease. A previously described transgenic CFH-gene deficient mouse model, (cfh-/-), shows hallmarks of early AMD. The ocular phenotype has been further analysed to demonstrate amyloid beta (Aβ) rich basement membrane deposits associated with activated complement C3. Cfh-/- mice were treated systemically in both prophylactic and therapeutic regimes with an anti-Aβ monoclonal antibody (mAb), 6F6, to determine the effect on the cfh-/- retinal phenotype. Prophylactic treatment with 6F6 demonstrated a dose dependent reduction in the accumulation of both Aβ and activated C3 deposition. A similar reduction in the retinal endpoints could be seen after therapeutic treatment. Serum Aβ levels after systemic administration of 6F6 show accumulation of Aβ in the periphery suggestive of a peripheral sink mechanism. In summary, anti-Aβ mAb treatment can partially prevent or reverse ocular phenotypes of the cfh-/- mouse. The data support this therapeutic approach in humans potentially modulating two key elements in the pathogenesis of AMD - Aβ and activated, complement C3.
authors.affiliation: Topical BioPharm Discovery Research and Development Unit, King of Prussia, Philadelphia, Pennsylvania, United States of America. ian.r.catchpole@gsk.com
authors.forename: Ian
authors.initials: I
authors.lastname: Catchpole
authors.forename: Volker
authors.initials: V
authors.lastname: Germaschewski
authors.forename: Jaimie
authors.initials: J
authors.lastname: Hoh Kam
authors.forename: Peter
authors.initials: P
authors.lastname: Lundh von Leithner
authors.forename: Susannah
authors.initials: S
authors.lastname: Ford
authors.forename: Gerald
authors.initials: G
authors.lastname: Gough
authors.forename: Peter
authors.initials: P
authors.lastname: Adamson
authors.forename: Philip
authors.initials: P
authors.lastname: Overend
authors.forename: Jan
authors.initials: J
authors.lastname: Hilpert
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López
authors.forename: Yin Shan Eric
authors.initials: YS
authors.lastname: Ng
authors.forename: Pete
authors.initials: P
authors.lastname: Coffey
authors.forename: Glen
authors.initials: G
authors.lastname: Jeffery
mesh_terms: D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D003176:Complement C3 / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D006825:Hybridomas; D008268:Macular Degeneration / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D012160:Retina / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D058846:Antibodies, Monoclonal, Murine-Derived; D003176:Complement C3; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)